Regulation of the hemostatic process provides for the rapid and appropriate mobilization of hemostasis after vascular trauma, yet maintains the fluidity of the blood under normal circumstances. Inappropriate expression of the hemostasis, however, plays an important role in the pathogenesis of atherosclerotic vascular disease and arterial and venous thrombosis. Normal hemostasis involves an interplay between platelet and endothelial cell function.. The program project consists of Five Projects and a core unit. Project 1 will use molecular genetic, biochemical, and biophysical techniques, to study the mechanism of activation of the platelet fibrinogen receptor, GPIIb-IIIa. Project 2 will study the molecular biology of GPIIb-IIIa, focusing on the regulation of GPIIb gene expression and on the genetic mechanisms responsible for case of Glanzmann's thrombasthenia. A new project for the Program, will study the role played by three isoforms of phosphatidylinositol 3-kinase in the signaling involved in platelet activation and megakaryocyte development. Project 4 will continue studies of the molecular basis of platelet activation, focusing on the structure and function of G-protein coupled receptors, downstream signaling between platelets, white cells and endothelial cells. Project 6 will study the biology of the platelet FcgammaRII receptor. Studies will examine the effects of cytokines and other biologic mediators of FcgammaRIIA transcription regulation, the effect of soluble FcgammaRIIA on platelet clearance in vivo caused by anti-platelet antibodies and immune complexes and on the role of Syk kinase in FcgammaRIIA-mediated signal transduction. These six projects are supported by core facilities providing for the production of monoclonal antibodies and for the overall administration of the Program.